Synthesis and antimicrobial activity of new series of thiazoles, pyridines and pyrazoles based on coumarin moiety

Microbial infections are currently a widespread disease in hospitals and community health centres and are a major cause of death worldwide. In pursuit of searching new antimicrobial agents, coumarin linked to thiazoles, pyridines and pyrazoles have been developed and evaluated for their antimicrobial properties against two Gram + bacteria, two Gram − bacteria as well as two fungi. Some of the prepared coumarins displayed high to moderate activity against the tested microorganisms with respect to the reference drugs. However, compound 3 exhibited antimicrobial effect equal to the reference drug Ciprofloxacin for Gram − baceria Enterobacter cloacae. Compound 12 was found to be the most potent compound against Bacillus pumilis with MIC of 7.69 (µmol/ml). Compounds 3, 4 and 12 showed remarkable activity against Streptococcus faecalis with MIC of 14.34, 3.67 and 15.36 (µmol/ml), respectively. Regarding Escherichia coli, most compounds recorded high to moderate MIC values (4.73–45.46 µmol/ml). Moreover, in case of E. cloacae compound 9 was the most potent compound with MIC value of 22.76 (µmol/ml).

Preliminary antimicrobial testing results (Table 1) demonstrated that thiazole derivative 3 having 5-phenyl azo group was high active against the two gram + bacteria with IZs of 20 and 20 mm and has the same IZ  Figure 5. Reaction of enaminone with uracil and pyrazole. , it was observed that compound 8 with CF 3 group attached to 2-position of pyridine ring showed high activity towards one bacteria and one fungi comparing with compounds 6 and 9 with CH 3 and C=O groups which was high active against one of tested bacteria. Potent antimicrobial effects were observed for compound 12 with ester group attached to 4-position of pyrazole ring towards all the tested pathogenic microbes (IZs = 19-21 mm) except with C. albicans whereas, pyrimidine thione 14 was high active only towards one bacteria and one fungi.

MIC and MBC.
The results for the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) (

Experimental protocols
General informations. All reagents and solvents were of commercial grade. Melting points of all the prepared coumarins were detected on an electro thermal apparatus and may be uncorrected. IR spectra were recorded using the Nicolet is 10 FTIR instrument in the wavenumber range of 4000-400 cm −1 . Some of 1 H and 13 C NMR data were measured with a Bruker Avance spectrometer (Bruker, Germany) at 400 and 100 MHz and others were measured with a Jeol spectrometer (Japan) at 500 and 125 MHz, respectively, using TMS as the internal standard. TMS was used as the internal standard and hydrogen coupling patterns were described as singlet    General method for the synthesis of compounds 6-9. A mixture of enaminone 5 (0.01 mol) and each of ethyl acetoacetate, acetylacetone, trifloroacetylacetone or ethyl cyanoacetate (0.01 mol) in acetic acid containing ammonium acetate was heated under reflux for 2 h. The colored solid obtained on hot was filtered, washed with ethanol, dried and recrystallized from DMF/EtOH mixture yielding the title compounds 6-9.    General method for the synthesis of pyrazoles 10a-c. To a mixture of the appropriate hydrazonoyl halide 2b-d (0.01 mol) and the enaminone 5 (0.01 mol) in dry benzene (10 ml), was added triethylamine (0.2 ml) and the mixture was refluxed for 2 h. The mixture was filtered on hot and let to cool, the precipitate obtained after cooling was washed with EtOH, dried and recrystallized from DMF/EtOH mixture. -2-oxo-2H-chromene-3-carbonyl)-1-phenyl-1H- -2-oxo-2H-chromene-3-carbonyl)-1-(4-nitro-phenyl)

Biological studies
Antimicrobial activity. Evaluation of the antimicrobial activity of the prepared compounds was performed against four bacteria and two fungal species using the agar plate diffusion method 57 . Penicillin G and ciprofloxacin were used as reference drugs for gram positive and gram negative bacteria, while ketoconazole was used as standard antifungal drug.

Conclusions
This study describes the activity of new coumarin-based thiazoles, pyridines and pyrazoles as antimicrobial agents. The newly synthesized compounds were screened for in vitro antimicrobial activity against two gram + bacteria, two gram -bacteria as well as two fungal strains.

Data availability
All data generated or analyzed during this study are included in this published article and its supplementary information file.